Tzeng Huey-En, Chang An-Chen, Tsai Chun-Hao, Wang Shih-Wei, Tang Chih-Hsin
Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.
Oncotarget. 2016 Jun 21;7(25):38566-38578. doi: 10.18632/oncotarget.9570.
A chondrosarcoma is a common, primary malignant bone tumor that can grow to destroy the bone, produce fractures and develop soft tissue masses. Left untreated, chondrosarcomas metastasize through the vascular system to the lungs and ultimately lead to large metastatic deposits of the malignant cartilage taking over lung volume and function. Vascular endothelial growth factor (VEGF)-C has been implicated in tumor-induced lymphangiogenesis and elevated expression of VEGF-C has been found to correlate with cancer metastasis. bFGF (basic fibroblast growth factor), a secreted cytokine, regulates biological activity, including angiogenesis and metastasis. We have previously reported on the important role of bFGF in angiogenesis in chondrosarcomas. However, the effect of bFGF in VEGF-C regulation and lymphangiogenesis in chondrosarcomas is poorly understood. In this investigation, we demonstrate a correlation exists between bFGF and VEGF-C in tissue specimens from patients with chondrosarcomas. To examine the lymphangiogenic effect of bFGF, we used human lymphatic endothelial cells (LECs) to mimic lymphatic vessel formation. We found that bFGF-treated chondrosarcomas promoted LEC tube formation and cell migration. In addition, bFGF knockdown inhibited lymphangiogenesis in vitro and in vivo. We also found that bFGF-induced VEGF-C is mediated by the platelet-derived growth factor receptor (PDGFR) and c-Src signaling pathway. Furthermore, bFGF inhibited microRNA-381 expression via the PDGFR and c-Src cascade. Our study is the first to describe the mechanism of bFGF-promoted lymphangiogenesis by upregulating VEGF-C expression in chondrosarcomas. Thus, bFGF could serve as a therapeutic target in chondrosarcoma metastasis and lymphangiogenesis.
软骨肉瘤是一种常见的原发性恶性骨肿瘤，它能够生长并破坏骨骼、导致骨折以及形成软组织肿块。若不进行治疗，软骨肉瘤会通过血管系统转移至肺部，最终导致大量恶性软骨转移灶占据肺容积并影响肺功能。血管内皮生长因子（VEGF）-C与肿瘤诱导的淋巴管生成有关，并且已发现VEGF-C的表达升高与癌症转移相关。碱性成纤维细胞生长因子（bFGF）是一种分泌性细胞因子，可调节包括血管生成和转移在内的生物学活性。我们之前曾报道过bFGF在软骨肉瘤血管生成中的重要作用。然而，bFGF在软骨肉瘤中对VEGF-C调节及淋巴管生成的影响尚不清楚。在本研究中，我们证实在软骨肉瘤患者的组织标本中bFGF与VEGF-C之间存在相关性。为了研究bFGF的淋巴管生成作用，我们使用人淋巴管内皮细胞（LEC）来模拟淋巴管形成。我们发现经bFGF处理的软骨肉瘤促进了LEC管形成和细胞迁移。此外，敲低bFGF在体外和体内均抑制了淋巴管生成。我们还发现bFGF诱导的VEGF-C是由血小板衍生生长因子受体（PDGFR）和c-Src信号通路介导的。此外，bFGF通过PDGFR和c-Src级联反应抑制微小RNA-381的表达。我们的研究首次描述了bFGF通过上调软骨肉瘤中VEGF-C的表达促进淋巴管生成的机制。因此，bFGF可作为软骨肉瘤转移和淋巴管生成的治疗靶点。
